Dopa Responsiveness in Parkinson's Disease.

BACKGROUND: Dopaminergic responsiveness is a defining feature of Parkinson's disease (PD). However, there is limited information on how this evolves over time. OBJECTIVES: To examine serial dopaminergic responses, if there are distinct patterns, and which factors predict these. METHODS: We analyzed data from the Parkinson's Progression Markers Initiative on repeated dopaminergic challenge tests (≥24.5% defined as a definite response). Growth-mixture modeling evaluated for different response patterns and multinomial logistic regression tested for predictors of these clusters. RESULTS: 1525 dopaminergic challenge tests were performed in 336 patients. At enrolment, mean age was 61.2 years (SD 9.6), 66.4% were male and disease duration was 0.5 years (SD 0.5). 1 to 2 years after diagnosis, 48.0% of tests showed a definite response, but this proportion increased with longer disease duration (51.1-74.3%). We identified 3 response groups: "Striking" (n = 29, 8.7%); "Excellent" (n = 110; 32.7%) and "Modest" (n = 197, 58.6%). Significant differences were as follows: striking responders commenced treatment earlier (P = 0.02), were less likely to be on dopamine agonist monotherapy (P = 0.01), and had better cognition (P < 0.01) and activities of daily living (P = 0.01). Excellent responders had higher challenge doses (P = 0.03) and were more likely to be on combination therapy (P < 0.01). CONCLUSION: Three distinct patterns of the dopaminergic response were observed. As the proportion of PD cases with definite dopa responsiveness increased over time, the initial treatment response may be an unreliable diagnostic aid.

Motor Complications in Parkinson's Disease: Results from 3343 Patients Followed for up to 12 Years.

BACKGROUND: Motor complications are well recognized in Parkinson's disease (PD), but their reported prevalence varies and functional impact has not been well studied. OBJECTIVES: To quantify the presence, severity, impact and associated factors for motor complications in PD. METHODS: Analysis of three large prospective cohort studies of recent-onset PD patients followed for up to 12 years. The MDS-UPDRS part 4 assessed motor complications and multivariable logistic regression tested for associations. Genetic risk score (GRS) for Parkinson's was calculated from 79 single nucleotide polymorphisms. RESULTS: 3343 cases were included (64.7% male). Off periods affected 35.0% (95% CI 33.0, 37.0) at 4-6 years and 59.0% (55.6, 62.3) at 8-10 years. Dyskinesia affected 18.5% (95% CI 16.9, 20.2) at 4-6 years and 42.1% (38.7, 45.5) at 8-10 years. Dystonia affected 13.4% (12.1, 14.9) at 4-6 years and 22.8% (20.1, 25.9) at 8-10 years. Off periods consistently caused greater functional impact than dyskinesia. Motor complications were more common among those with higher drug doses, younger age at diagnosis, female gender, and greater dopaminergic responsiveness (in challenge tests), with associations emerging 2-4 years post-diagnosis. Higher Parkinson's GRS was associated with early dyskinesia (0.026 ≤ P ≤ 0.050 from 2 to 6 years). CONCLUSIONS: Off periods are more common and cause greater functional impairment than dyskinesia. We confirm previously reported associations between motor complications with several demographic and medication factors. Greater dopaminergic responsiveness and a higher genetic risk score are two novel and significant independent risk factors for the development of motor complications.

Impaired value-based decision-making in Parkinson's disease apathy.

Apathy is a common and disabling complication of Parkinson's disease characterized by reduced goal-directed behaviour. Several studies have reported dysfunction within prefrontal cortical regions and projections from brainstem nuclei whose neuromodulators include dopamine, serotonin and noradrenaline. Work in animal and human neuroscience have confirmed contributions of these neuromodulators on aspects of motivated decision-making. Specifically, these neuromodulators have overlapping contributions to encoding the value of decisions, and influence whether to explore alternative courses of action or persist in an existing strategy to achieve a rewarding goal. Building upon this work, we hypothesized that apathy in Parkinson's disease should be associated with an impairment in value-based learning. Using a four-armed restless bandit reinforcement learning task, we studied decision-making in 75 volunteers; 53 patients with Parkinson's disease, with and without clinical apathy, and 22 age-matched healthy control subjects. Patients with apathy exhibited impaired ability to choose the highest value bandit. Task performance predicted an individual patient's apathy severity measured using the Lille Apathy Rating Scale (R = -0.46, P < 0.001). Computational modelling of the patient's choices confirmed the apathy group made decisions that were indifferent to the learnt value of the options, consistent with previous reports of reward insensitivity. Further analysis demonstrated a shift away from exploiting the highest value option and a reduction in perseveration, which also correlated with apathy scores (R = -0.5, P < 0.001). We went on to acquire functional MRI in 59 volunteers; a group of 19 patients with and 20 without apathy and 20 age-matched controls performing the Restless Bandit Task. Analysis of the functional MRI signal at the point of reward feedback confirmed diminished signal within ventromedial prefrontal cortex in Parkinson's disease, which was more marked in apathy, but not predictive of their individual apathy severity. Using a model-based categorization of choice type, decisions to explore lower value bandits in the apathy group activated prefrontal cortex to a similar degree to the age-matched controls. In contrast, Parkinson's patients without apathy demonstrated significantly increased activation across a distributed thalamo-cortical network. Enhanced activity in the thalamus predicted individual apathy severity across both patient groups and exhibited functional connectivity with dorsal anterior cingulate cortex and anterior insula. Given that task performance in patients without apathy was no different to the age-matched control subjects, we interpret the recruitment of this network as a possible compensatory mechanism, which compensates against symptomatic manifestation of apathy in Parkinson's disease.